Several investigators have suggested that gender differences in vulnerability to development of the mood disorders of depression and anxiety are linked to fluctuating gonadal hormone levels that occur during the female reproductive cycle, the onset of puberty and/or menopause. Other investigators have suggested an association between brain serotonin (5-HT) and the pathogenesis of depression. It is, therefore, possible that hormonal modulation of the serotonergic system contributes to the female's vulnerability to depression and anxiety. Although there is evidence that 5-HT levels, turnover, and function are modulated by estrogen and progesterone, mechanistic explanations for the modulation have not been forthcoming. In early studies, an estrogen-induced modulation of serotonin receptors was implicated, but these studies were completed prior to the recognition of the many receptor subtypes on which 5-HT acts. Few neurochemical/molecular studies have been designed to examine the effects of estrogen on select serotonin receptor subtypes and their interactions. However, results of behavioral studies have led to the suggestion that estrogen may modulate serotonin by altering the functional balance among the different receptor subtypes. The present project is designed to test the hypothesis that estrogen alters the balance between select serotonin receptor subtypes and thereby alters behavioral events that are modulated by the 5-HT system.